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Mechanoadaptation and Caveolae Biology

Mechanoadaptation and Caveolae Biology

Signals are the language of life, mediating the communication essential for cells proper behavior.

Within cells, intricate networks of proteins transduce signals into the appropriate physiological response, and many diseases are caused by malfunctioning of these signal transduction networks. Our interest is in the mechanisms through which integrins, Rho/Rac GTPases and caveolin cooperate to regulate gene expression, cell cycle progression, migration, polarization, vesicle trafficking and epithelial-mesenchymal transition (EMT), key processes in the pathogenesis of cancer and inflammatory and cardiovascular diseases.

Integrins (the main ECM receptors) regulate caveolinmediated endocytosis of Rac binding sites within cholesterolenriched membrane microdomains (CEMM). Our recent work shows that cells lacking caveolin exit quiescence and progress through the cell cycle faster than wild-type cells, and are able to proliferate without anchorage to substrate and do not show the normal downregulation of cyclin D1 upon serum deprivation or detachment. Surprisingly, this proliferative advantage is independent of ErkMAPK, being instead driven by increased membrane order and Rac membrane targeting. We are currently assessing the contribution of this mechanism to atherogenesis.

A related interest is the influence of caveolin on cell polarity and directional migration. Caveolin regulates these processes in 2D, through coordination of Src kinase and Rho GTPase signaling. We are investigating how this regulation operates in 3D, focusing on the contribution of caveolin to 3D microenvironment remodeling.

To understand the molecular mechanisms by which integrins regulate caveolin trafficking, we are studying actin polymerization pathways that control caveolae dynamics, and we are also conducting an RNAi-based genome-wide highcontent image analysis screen in collaboration with the Cellomics Unit.

Our work on EMT has identified a role for ERK/NF-kB/Snail1 signaling, and we are currently studying signaling pathways underlying EMT and fibrosis during chronic peritoneal inflammation.